Creating supersaturated solutions of celecoxib “Cel” has been shown to increase the rate and extent of drug absorption.2 Such increases offer the possibility of formulations using less drug and/or achieving faster pain relief from this COX-2 inhibitor. Combining a sodium salt of Cel with polyether surfactants was found to be particularly effective: the duration of supersaturation increased from less than one minute for the salt alone to greater than 60 minutes for the mixtures; plasma concentrations were higher after 30 minutes for the mixtures than they were after even 2 hours for the marketed formulation; and total drug absorption increased from around 40% to nearly 100%.2 Since Cel is a weak acid with a pKa of 11.1,14 its salts are neutralized rapidly in aqueous suspension at physiological pH (pH ˜1-7), and the neutral drug crystallizes rapidly. Therefore, the observed improvements are believed to require both a starting form that cannot easily revert to the thermodynamically stable form of Cel (Cel-III) without first dissolving, and another molecule that will solvate the dissolved Cel to prevent or slow down the precipitation of Cel-III.
It has been shown that the bioavailability of Cel can be enhanced by dosing forms that are transiently more soluble than the marketed crystalline form, Cel-III.1-4 The low solubility of Cel-III, limits both the rate and extent of absorption after dosing. Published strategies showing improvement in solubility and/or bioavailability of Cel have included co-crystals, salt forms, metastable polymorphs, amorphous dispersions and solutions in organic vehicles.1-3, 7, 8 For example, U.S. Pat. No. 7,927,613 to Almarsson et al. discloses co-crystals comprising (1) celecoxib and nicotinamide and (2) celecoxib and 18-crown-6; and U.S. Pat. No. 7,790,905 to Tawa et al. discloses a propylene glycol solvate of a sodium salt of celecoxib, and in particular, a propylene glycol solvate of celecoxib sodium trihydrate.
Although it was known that the hydrated sodium salt of celecoxib gained and lost waters of hydration rapidly as a function of relative humidity “RH”, there was no structural basis to understand this dynamic behavior. Sodium salts of other drug molecules with variable hydration behavior are known.9,10 Several studies have shown “tailor-made” additives to successfully inhibit growth along specific crystal faces in order to modify habit.11-13 A study by Davey et al. showed that the presence of alkanoic acids could modify the habit of the dicarboxylic acid, adipic acid. In this study, alcohols were added to crystallization media in an attempt to slow growth by inhibiting hydration of the sodium ion.
In accordance with the present invention, crystallization of the hydrated sodium salt of celecoxib with benzyl alcohol enabled structural determination of celecoxib sodium pentahydrate (Cel-Na(H2O)5), a structure which proved useful to the understanding of the complex physical behavior of Cel-Na.